Morbid obesity is an important public health problem, but the complex relationship between obesity and the skeleton is poorly understood. This proposal has been designed to examine the impact of obesity and obesity treatments on skeletal health, and to facilitate my long-term goal of becoming an independent clinical investigator. Recent epidemiologic data suggest that fracture rates in morbidly obese adults are higher than is commonly believed, and may equal or surpass rates in normal-weight adults at certain skeletal sites. Furthermore, Roux-en-Y gastric bypass surgery is becoming increasingly popular as a treatment for morbid obesity, but there is growing concern that the surgery results in accelerated bone loss and increased risk of fractures. Our knowledge in this field has been complicated by known limitations in dual-energy x-ray absorptiometry in obesity and during weight loss. This proposal seeks to provide a more complete and accurate evaluation of bone density, microarchitecture, and strength in both obesity and after gastric bypass surgery using advanced imaging techniques. A prospective, longitudinal cohort of morbidly obese adults will be studied before and for 2 years after gastric bypass surgery using quantitative computed tomography and high- resolution non-invasive imaging. Normal-weight and non-surgical obese controls will be recruited for cross-sectional and longitudinal comparisons. We will also examine the complex physiology connecting adipose tissue and the skeleton, and evaluate potential mechanisms of accelerated bone loss after gastric bypass. The career development plan consists of a five year mentored program that will incorporate didactic and research training and will be guided by well-established scientists who have been selected based upon their expertise in obesity and metabolic bone disease. In summary, the proposed research will test innovative hypotheses about the skeletal consequences of obesity and gastric bypass surgery, while providing a training platform and investigational niche for the candidate to establish independence as a clinical investigator. Characterization of obesity's effects on bone may yield insights on how to optimize skeletal health in obese patients, uncover ways to minimize fracture risk for patients undergoing gastric bypass surgery, and shed light on the complex interactions between adipose tissue and bone.